Restoring myocardial infarction-induced long-term memory impairment by targeting the cystic fibrosis transmembrane regulator.

BACKGROUND: Cognitive impairment is a serious comorbidity in heart failure patients, but effective therapies are lacking. We investigated the mechanisms that alter hippocampal neurons following myocardial infarction (MI). METHODS: MI was induced in male C57Bl/6 mice by left anterior descending coronary artery ligation. We utilised standard procedures to measure cystic fibrosis transmembrane regulator (CFTR) protein levels, inflammatory mediator expression, neuronal structure, and hippocampal memory. Using in vitro and in vivo approaches, we assessed the role of neuroinflammation in hippocampal neuron degradation and the therapeutic potential of CFTR correction as an intervention. FINDINGS: Hippocampal dendrite length and spine density are reduced after MI, effects that associate with decreased neuronal CFTR expression and concomitant microglia activation and inflammatory cytokine expression. Conditioned medium from lipopolysaccharide-stimulated microglia (LCM) reduces neuronal cell CFTR protein expression and the mRNA expression of the synaptic regulator post-synaptic density protein 95 (PSD-95) in vitro. Blocking CFTR activity also down-regulates PSD-95 in neurons, indicating a relationship between CFTR expression and neuronal health. Pharmacologically correcting CFTR expression in vitro rescues the LCM-mediated down-regulation of PSD-95. In vivo, pharmacologically increasing hippocampal neuron CFTR expression improves MI-associated alterations in neuronal arborisation, spine density, and memory function, with a wide therapeutic time window. INTERPRETATION: Our results indicate that CFTR therapeutics improve inflammation-induced alterations in hippocampal neuronal structure and attenuate memory dysfunction following MI. FUNDING: Knut and Alice Wallenberg Foundation [F 2015/2112]; Swedish Research Council [VR; 2017-01243]; the German Research Foundation [DFG; ME 4667/2-1]; Hjärnfonden [FO2021-0112]; The Crafoord Foundation; Åke Wibergs Stiftelse [M19-0380], NMMP 2021 [V2021-2102]; the Albert Påhlsson Research Foundation; STINT [MG19-8469], Lund University; Canadian Institutes of Health Research [PJT-153269] and a Heart and Stroke Foundation of Ontario Mid-Career Investigator Award.

Amyloid ß1-42-Induced Rapid Zn2+ Influx into Dentate Granule Cells Attenuates Maintained LTP Followed by Retrograde Amnesia.

On the basis of the evidence that amyloid ß1-42 (Aß1-42)-induced Zn2+ influx affects memory acquisition via attenuated long-term potentiation (LTP) induction, here we tested whether Aß1-42-induced Zn2+ influx affects maintained LTP in freely moving rats, resulting in retrograde amnesia. Both maintained LTP and space memory were impaired by local injection of 250 µM ZnCl2 (2 µl) into the dentate gyrus, while maintained LTP was impaired by injection of either Aß1-40 or Aß1-42 (25 µM, 2 µl) into the dentate gyrus. Aß1-40-induced impairment of maintained LTP was rescued by co-injection of CaEDTA, an extracellular Zn2+ chelator, but not by co-injection of ZnAF-2DA, an intracellular Zn2+ chelator, suggesting that maintained LTP is impaired by Aß1-40 via a mechanism that may involve extracellular Zn2+. In contrast, Aß1-42-induced impairments of maintained LTP and space memory were rescued by co-injection of either CaEDTA or ZnAF-2DA. Intracellular Zn2+ in dentate granule cells was rapidly increased by Aß1-42 injection into the dentate gyrus, but not by Aß1-40 injection. The block of Aß1-42-induced increase in intracellular Zn2+ by pretreatment with dexamethasone, a metallothionein inducer also rescued Aß1-42-induced impairment of maintained LTP. The present study indicates that Aß1-42-induced Zn2+ influx into dentate granule cells, which more readily occurs than free Zn2+-induced Zn2+ influx, attenuates maintained LTP followed by retrograde amnesia. It is likely that controlling Aß1-42-induced intracellular Zn2+ dysregulation is a strategy for defending AD pathogenesis.

Postischemic fish oil treatment restores long-term retrograde memory and dendritic density: An analysis of the time window of efficacy.

We reported that fish oil (FO) prevented the loss of spatial memory caused by transient, global cerebral ischemia (TGCI), provided the treatment covered the first days prior to and after ischemia. Continuing these studies, trained rats were subjected to TGCI, and FO was administered for 10days, with a time window of efficacy (TWE) of 4, 8 or 12h post-ischemia. Retrograde memory was assessed up to 43days after TGCI. In another experiment, ischemic rats received FO with a 4- or 12-h TWE, and dendritic density was assessed in the hippocampus and cerebral cortex. The brain lipid profile was evaluated in sham-operated and ischemic rats that were treated with FO or vehicle with a 4-h TWE. Ischemia-induced retrograde amnesia was prevented by FO administration that was initiated with either a 4- or 8-h TWE. Fish oil was ineffective after a 12-h TWE. Independent of the TWE, FO did not prevent ischemic neuronal death. In the hippocampus, but not cerebral cortex, TGCI-induced dendritic loss was prevented by FO with a 4-h TWE but not 12-h TWE. The level of docosahexaenoic acid almost doubled in the hippocampus in ischemic, FO-treated rats (4-h TWE). The data indicate that (i) the anti-amnesic effect of FO can be observed with a TWE of up to 8h, (ii) the stimulation of dendritic neuroplasticity may have contributed to this effect, and (iii) DHA in FO may be the main active constituent in FO that mediates the cognitive and neuroplasticity effects on TGCI.

Memory engram storage and retrieval.

A great deal of experimental investment is directed towards questions regarding the mechanisms of memory storage. Such studies have traditionally been restricted to investigation of the anatomical structures, physiological processes, and molecular pathways necessary for the capacity of memory storage, and have avoided the question of how individual memories are stored in the brain. Memory engram technology allows the labeling and subsequent manipulation of components of specific memory engrams in particular brain regions, and it has been established that cell ensembles labeled by this method are both sufficient and necessary for memory recall. Recent research has employed this technology to probe fundamental questions of memory consolidation, differentiating between mechanisms of memory retrieval from the true neurobiology of memory storage.

Clinical characteristics and brain PET findings in 3 cases of dissociative amnesia: disproportionate retrograde deficit and posterior middle temporal gyrus hypometabolism.

BACKGROUND: Precipitated by psychological stress, dissociative amnesia occurs in the absence of identifiable brain damage. Its clinical characteristics and functional neural basis are still a matter of controversy. METHODS: In the present paper, we report 3 cases of retrograde autobiographical amnesia, characterized by an acute onset concomitant with emotional/neurological precipitants. We present 2 cases of dissociative amnesia with fugue (cases 1 and 2), and one case of focal dissociative amnesia after a minor head trauma (case 3). The individual case histories and neuropsychological characteristics are reported, as well as the whole-brain voxel-based 18FDG-PET metabolic findings obtained at group-level in comparison to 15 healthy subjects. RESULTS: All patients suffered from autobiographical memory loss, in the absence of structural lesion. They had no significant impairment of anterograde memory or of executive function. Impairment of autobiographical memory was complete for two of the three patients, with loss of personal identity (cases 1 and 2). A clinical recovery was found for the two patients in whom follow-up was available (cases 2 and 3). Voxel-based group analysis highlighted a metabolic impairment of the right posterior middle temporal gyrus. 18FDG-PET was repeated in case 3, and showed a complete functional brain recovery. CONCLUSION: The situation of dissociative amnesia with disproportionate retrograde amnesia is clinically heterogeneous between individuals. Our findings may suggest that impairment of high-level integration of visual and/or emotional information processing involving dysfunction of the right posterior middle temporal gyrus could reduce triggering of multi-modal visual memory traces, thus impeding reactivation of aversive memories.

Altered anterior cingulate neurochemistry in emerging adult binge drinkers with a history of alcohol-induced blackouts.

BACKGROUND: Binge alcohol consumption is associated with multiple neurobiological consequences, including altered neurophysiology, brain structure, and functional activation. Magnetic resonance spectroscopy (MRS) studies have demonstrated neurochemical alterations in the frontal lobe of alcohol users, although most studies focused on older, alcohol-dependent subjects. METHODS: In this study, neurochemical data were acquired using MRS at 4.0 Tesla from emerging adults (18 to 24 years old) who were binge alcohol drinkers (BD, n = 23) or light drinkers (LD, n = 31). Since binge drinking is also associated with increased prevalence of experiencing an alcohol-induced blackout, BD were stratified into alcohol-induced blackout (BDBO) and non-blackout (BDN) groups. RESULTS: Overall, BD had significantly lower gamma amino-butyric acid (GABA) and N-acetyl-aspartate (NAA) in the anterior cingulate cortex (ACC) than LD. When stratified by blackout history, BDBO also had lower ACC glutamate (Glu) than LD. No group differences in MRS metabolites were observed in the parietal-occipital cortex. Lower ACC GABA and Glu remained significant after accounting for lower gray matter content in BD, however, NAA differences were no longer evident. In addition, low ACC GABA levels were associated with greater alcohol use consequences, and worse response inhibition and attention/mental flexibility in BD. CONCLUSIONS: These data indicate that binge drinking affects frontal lobe neurochemistry, more so in those who had experienced an alcohol-induced blackout. Characterization of the neurochemical profiles associated with binge alcohol consumption and blackout history may help identify unique risk factors for the later manifestation of alcohol abuse and dependence, in young individuals who are heavy, frequent drinkers, but who do not meet the criteria for alcohol abuse disorders.

Postconcussion syndrome and mild head injury: the role of early diagnosis using neuropsychological tests and functional magnetic resonance/spectroscopy.

OBJECTIVE: Postconcussion syndrome (PCS) is usually underestimated in cases of mild head injury (MHI). It is one of the most common causes of physical, cognitive, and psychomotor disturbances that affect the quality of life, work, and social reintegration of individuals. Until now, we did not have evidence of structural abnormalities shown by traditional imaging methods. We describe a series of instruments that confirm PCS with satisfactory evidence. METHODS: We conducted a clinical prospective study of 19 adult patients selected from a pool of 320 adults who had MHI. The cognitive, executive, and memory functions of subjects were examined within the first 72 hours using neuropsychological tests. These results were analyzed with neurological examination and functional MR/spectroscopy. RESULTS: Neurobehavioral alterations were found in 47% of cases, with posttraumatic amnesia. Around 55% of subjects experienced physical disturbances such as headache and postural vertigo due to PCS. The spectroscopy reports revealed neurometabolite disturbances in 54% of cases, particularly N-acetylaspartate (Naa) and the Naa/lactate ratio in the frontal lobe. We observed a relationship between metabolite disturbances in spectroscopy and the digit span backward test (P = .045). CONCLUSIONS: This first diagnostic strategy supports with scientific evidence the presence of PCS in MHI. We identified physical and neuropsychological abnormalities from this group, affecting the areas of memory and learning. Evidence of neurometabolite disturbances were found specifically in the frontal lobe. It is necessary to complete comparative follow-up for an extended period of time. The neuropsychological and spectroscopy tests allow us to confirm the diagnosis of a syndrome that is usually neglected.

Nootropic activity of Celastrus paniculatus seed.

The effect of Celastrus paniculatus Willd. (Celastraceae) seed aqueous extract on learning and memory was studied using elevated plus maze and passive avoidance test (sodium nitrite induced amnesia rodent model). The aqueous seed extract was administered orally in two different doses to rats (350 and 1050 mg/kg) and to mice (500 and 1500 mg/kg). The results were compared to piracetam (100 mg/kg, p.o.) used as a standard drug. Chemical hypoxia was induced by subcutaneous administration of sodium nitrite (35 mg/kg), immediately after acquisition training. In elevated plus maze and sodium nitrite-induced amnesia model, Celastrus paniculatus extract has showed statistically significant improvement in memory process when compared to control. The estimation of acetylcholinesterase enzyme in rat brain supports the plus maze and passive avoidance test by reducing acetylcholinesterase activity which helps in memory performance. The study reveals that the aqueous extract of Celastrus paniculatus seed has dose-dependent cholinergic activity, thereby improving memory performance. The mechanism by which Celastrus paniculatus enhances cognition may be due to increased acetylcholine level in rat brain.

Emotion-induced retrograde amnesia varies as a function of noradrenergic-glucocorticoid activity.

RATIONALE: Privileged episodic encoding of an aversive event often comes at a cost of neutral events flanking the aversive event, resulting in decreased episodic memory for these neutral events. This peri-emotional amnesia is amygdala-dependent and varies as a function of norepinephrine activity. However, less is known about the amnesiogenic potential of cortisol. OBJECTIVE: We used a strategy of pharmacologically potentiating cortisol and norepinephrine activity to probe the putative neurochemical substrates of peri-emotional amnesia. MATERIALS AND METHODS: Fifty-four healthy individuals participated in a randomized double-blind placebo-controlled study. Within the experimental context of an established peri-emotional amnesia paradigm, we tested the amnesiogenic potential of hydrocortisone (30 mg p.o.) in the presence or absence of the norepinephrine-reuptake inhibitor reboxetine (4 mg p.o.). RESULTS: Under dual challenge conditions, we observed a linear dose-response relationship in the magnitude and duration of emotion-induced retrograde amnesia. CONCLUSIONS: Our results are consistent with a phenotypic expression of retrograde amnesia varying as a function of norepinephrine and cortisol coactivation during episodic encoding of aversive events. Our study demonstrates that the adverse cognitive and behavioral sequelae of aversive emotion can be experimentally modeled by a pharmacological manipulation of its putative neurochemical substrates.

Persistent autobiographical amnesia: a case report.

We describe a 47-year-old man who referred to the Emergency Department for sudden global amnesia and left mild motor impairment in the setting of increased arterial blood pressure. The acute episode resolved within 24 hours. Despite general recovery and the apparent transitory nature of the event, a persistent selective impairment in recollecting events from some specific topics of his personal life became apparent. Complete neuropsychological tests one week after the acute onset and 2 months later demonstrated a clear retrograde memory deficit contrasting with the preservation of anterograde memory and learning abilities. One year later, the autobiographical memory deficit was unmodified, except for what had been re-learnt. Brain MRI was normal while H20 brain PET scans demonstrated hypometabolism in the right globus pallidus and putamen after 2 weeks from onset, which was no longer present one year later. The absence of a clear pathomechanism underlying focal amnesia lead us to consider this case as an example of functional retrograde amnesia.

The many faces of amnesia.

Results from studies of retrograde amnesia provide much of the evidence for theories of memory consolidation. Retrograde amnesia gradients are often interpreted as revealing the time needed for the formation of long-term memories. The rapid forgetting observed after many amnestic treatments, including protein synthesis inhibitors, and the parallel decay seen in long-term potentiation experiments are presumed to reveal the duration of short-term memory processing. However, there is clear and consistent evidence that the time courses obtained in these amnesia experiments are highly variable within and across experiments and treatments. The evidence is inconsistent with identification of basic temporal properties of memory consolidation. Alternative views include modulation of memory and emphasize the roles that hormones and neurotransmitters have in regulating memory formation. Of related interest, converging lines of evidence suggest that inhibitors of protein synthesis and of other biochemical processes act on modulators of memory formation rather than on mechanisms of memory formation. Based on these findings, memory consolidation and reconsolidation studies might better be identified as memory modulation and "remodulation" studies. Beyond a missing and perhaps unattainable time constant of memory consolidation, some current views of memory consolidation assume that memories, once formed, are generally unmodifiable. It is this perspective that appears to have led to the recent interest in memory reconsolidation. But the view adopted here is that memories are continually malleable, being updated by new experiences and, at the same time, altering the memories of later experiences. Studies of memory remodulation offer promise of understanding the neurobiological bases by which new memories are altered by prior experiences and by which old memories are altered by new experiences.

Persistent disruption of an established morphine conditioned place preference.

In human addicts, craving and relapse are frequently evoked by the recall of memories connected to a drug experience. Established memories can become labile if recalled and can then be disrupted by several interfering events and pharmacological treatments, including inhibition of protein synthesis. Thus, reactivation of mnemonic traces provides an opportunity for disrupting memories that contribute to pathological states. Here, we tested whether the memory of a drug experience can be weakened by inhibiting protein synthesis after the reactivation of its trace. We found that an established morphine conditioned place preference (mCPP) was persistently disrupted if protein synthesis was blocked by either anisomycin or cycloheximide after the representation of a conditioning session. Unlike other types of memories, an established mCPP did not become labile after contextual recall, but required the concomitant re-experience of both the conditioning context and the drug. An established mCPP was disrupted after the conditioning session if protein synthesis was blocked selectively in the hippocampus, basolateral amygdala, or nucleus accumbens but not in the ventral tegmental area. This disruption seems to be permanent, because the preference did not return after further conditioning. Thus, established memories induced by a drug of abuse can be persistently disrupted after reactivation of the conditioning experience.

Cellular and systems reconsolidation in the hippocampus.

Cellular theories of memory consolidation posit that new memories require new protein synthesis in order to be stored. Systems consolidation theories posit that the hippocampus has a time-limited role in memory storage, after which the memory is independent of the hippocampus. Here, we show that intra-hippocampal infusions of the protein synthesis inhibitor anisomycin caused amnesia for a consolidated hippocampal-dependent contextual fear memory, but only if the memory was reactivated prior to infusion. The effect occurred even if reactivation was delayed for 45 days after training, a time when contextual memory is independent of the hippocampus. Indeed, reactivation of a hippocampus-independent memory caused the trace to again become hippocampus dependent, but only for 2 days rather than for weeks. Thus, hippocampal memories can undergo reconsolidation at both the cellular and systems levels.

Retrograde amnesia for spatial memory induced by NMDA receptor-mediated long-term potentiation.

If information is stored as distributed patterns of synaptic weights in the hippocampal formation, retention should be vulnerable to electrically induced long-term potentiation (LTP) of hippocampal synapses after learning. This prediction was tested by training animals in a spatial water maze task and then delivering bursts of high-frequency (HF) or control stimulation to the perforant path in the angular bundle. High-frequency stimulation induced LTP in the dentate gyrus and probably also at other hippocampal termination sites. Retention in a later probe test was disrupted. When the competitive NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) was administered before the high-frequency stimulation, water maze retention was unimpaired. CPP administration blocked the induction of LTP. Thus, high-frequency stimulation of hippocampal afferents disrupts memory retention only when it induces a change in the spatial pattern of synaptic weights. The NMDA receptor dependency of this retrograde amnesia is consistent with the synaptic plasticity and memory hypothesis.

The ubiquitin-proteasome cascade is required for mammalian long-term memory formation.

It has been recently demonstrated that ubiquitin-proteasome-mediated proteolysis is required for long-term synaptic facilitation in Aplysia. Here we show that the hippocampal blockade of this proteolytic pathway is also required for the formation of long-term memory in the rat. Bilateral infusion of lactacystin, a specific proteasome inhibitor, to the CA1 region caused full retrograde amnesia for a one-trial inhibitory avoidance learning when given 1, 4 or 7h, but not 10 h, after training. Proteasome inhibitor I produced similar effects. In addition, inhibitory avoidance training resulted in an increased ubiquitination and 26S proteasome proteolytic activity and a decrease in the levels of IkappaB, a substrate of the ubiquitin-proteasome cascade, in hippocampus 4 h after training. Together, these findings indicate that the ubiquitin-proteasome cascade is crucial for the establishment of LTM in the behaving animal.

Phosphorylated cAMP response element-binding protein as a molecular marker of memory processing in rat hippocampus: effect of novelty.

From mollusks to mammals the activation of cAMP response element-binding protein (CREB) appears to be an important step in the formation of long-term memory (LTM). Here we show that a 5 min exposure to a novel environment (open field) 1 hr after acquisition of a one-trial inhibitory avoidance training hinders both the formation of LTM for the avoidance task and the increase in the phosphorylation state of hippocampal Ser 133 CREB [phosphorylated CREB (pCREB)] associated with the avoidance training. To determine whether this LTM deficit is attributable to the reduced pCREB level, rats were bilaterally cannulated to deliver Sp-adenosine 3', 5'-cyclic monophosphothioate (Sp-cAMPS), an activator of PKA. Infusion of Sp-Adenosine 3',5'-cyclic monophosphothioate Sp-cAMPS to CA1 region increased hippocampal pCREB levels and restored normal LTM of avoidance learning in rats exposed to novelty. Moreover, a 5 min exposure to the open field 10 min before the avoidance training interferes with the amnesic effect of a second 5 min exposure to the open field 1 hr after avoidance training and restores the hippocampal levels of pCREB. In contrast, the avoidance training-associated activation of extracellular signal-regulated kinases (p42 and p44 mitogen-activated protein kinases) in the hippocampus is not altered by novelty. Together, these findings suggest that novelty regulates LTM formation by modulating the phosphorylation state of CREB in the hippocampus.

Anesthesia induced retrograde amnesia is ameliorated by ephrinA5-IgG in mice: EphA receptor tyrosine kinases are involved in mammalian memory.

EphA receptors and their ephrin-A ligands were previously thought to play a role only in embryonic development of the brain. Recently, however, these proteins were shown to be expressed in the adult mouse brain, primarily in the hippocampus, and were implicated in hippocampal synaptic plasticity and learning. What aspects of learning EphA receptors mediate have not been studied? Using the fear conditioning paradigm we demonstrate that EphA receptors play roles in memory. We show that post-training surgical anesthesia leads to robust context specific retrograde amnesia in mice, and post-anesthesia activation of EphA receptors induces a significant amelioration of this amnesia. As acquisition was left unaffected and performance factors were found unaltered, we suggest that the amelioration was due to changes in cognition leading to improved memory. Our data represent the first pieces of evidence for the involvement of EphA receptor tyrosine kinase receptors in mammalian memory, a finding that opens a new avenue into the functional analysis of the largest receptor tyrosine kinase subfamily in the brain.

Primary amnesia of insidious onset with subsequent stabilisation.

A patient had a slowly developing amnesic syndrome that remained substantially unchanged during the two and a half years of observation. Intellectual skills were excellent and there was no language, perception, praxis, or calculation deficit. The memory impairment involved verbal and visual learning, sparing spatial learning and, to a large extent, retrograde memory. Magnetic resonance imaging was normal, but PET showed a hypometabolism of the left temporal mesial region and thalamus. This case extends the spectrum of monosymptomatic cognitive disorders, previously reported in the area of language, praxis, and visual recognition, to amnesia.

Regional cerebral blood flow and metabolism in patients with transient global amnesia: a positron emission tomography study.

In four patients who experienced transient global amnesia (TGA), clinical features and neuroradiological findings including positron emission tomography (PET) were studied within three months of the episodes, and compared with those in seven cases with cerebral transient ischaemic attacks (TIA). None of TGA patients had a previous history or significant risk factors for the cerebrovascular diseases. Their electroencephalogram, brain CT and angiogram for the head and neck were almost normal. PET study showed better preserved cerebral blood flow and oxygen metabolism in each area of the brain in patients with TGA compared with those with TIA in whom focal reductions of flow and metabolism were evident. These observations suggest that TGA is caused by reversible circulatory and/or metabolic disturbance, of which mechanism might be different from that in TIA.